The goal of this research is to develop a series of interconnected models of therapeutic response in the diseased lung, focused primarily on cystic fibrosis (CF), that will ultimately provide a means for predicting in vivo response based on patient-specific in vitro testing, allowing for the optimization and personalization of therapies. Our center has an extensive history with the use of human bronchial epithelial (HBE) and more recently human nasal epithelial (HNE) cell cultures to study CF pathophysiology. We have also developed functional imaging biomarkers in the lung that provide organ level quantification of CF lung physiology (mucociliary clearance and airway liquid absorption). More recently we have developed in silico systems models of lung physiology at both the cell and organ level. The in silico models provide a framework of differential equations that describe how basic physiological processes interact and contribute to experimental outcomes. Their use allows these mechanisms to be more specifically differentiated. Here we propose to link in vitro and in vivo response by sampling and culturing human nasal epithelial (HNE) cell cultures from both non-CF and CF subjects who will also perform a series of physiological assessments, including functional imaging scans. Our in silico models will facilitate this linking of these models. We wil also retrospectively and prospectively survey clinical data from donors to determine which measures of cell and organ level physiology will predict the clinical course of CF lung disease.